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The Journal of Neuroscience, March 2, 2005, 25(9):2295-2303; doi:10.1523/JNEUROSCI.5107-04.2005

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Neurobiology of Disease
ets-2 Promotes the Activation of a Mitochondrial Death Pathway in Down's Syndrome Neurons

Pablo Helguera,^1 * Alejandra Pelsman,^1 * Gustavo Pigino,⁴ Ernst Wolvetang,⁵ Elizabeth Head,^2,3 and Jorge Busciglio^1,3

Departments of ¹Neurobiology and Behavior and ²Neurology and ³Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California 92697, ⁴Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois 60612, and ⁵Centre for Functional Genomics and Human Disease, Monash University, Clayton 3168, Australia

Down's syndrome (DS) is characterized by mental retardation and development of Alzheimer's disease (AD). Oxidative stress and mitochondrial dysfunction are both related to neurodegeneration in DS. Several genes in chromosome 21 have been linked to neuronal death, including the transcription factor ets-2. Cortical cultures derived from normal and DS fetal brains were used to study the role of ets-2 in DS neuronal degeneration. ets-2 was expressed in normal human cortical neurons (HCNs) and was markedly upregulated by oxidative stress. When overexpressed in normal HCNs, ets-2 induced a stereotyped sequence of apoptotic changes leading to neuronal death. DS HCNs exhibit intracellular oxidative stress and increased apoptosis after the first week in culture (Busciglio and Yankner, 1995). ets-2 levels were increased in DS HCNs, and, between 7 and 14 d in vitro, DS HCNs showed increased bax, cytoplasmic translocation of cytochrome c and apoptosis inducing factor, and active caspases 3 and 7, consistent with activation of an apoptotic mitochondrial death pathway. Degeneration of DS neurons was reduced by dominant-negative ets-2, suggesting that increased ets-2 expression promotes DS neuronal apoptosis. In the human brain, ets-2 expression was found in neurons and astrocytes. Strong ets-2 immunoreactivity was observed in DS/AD and sporadic AD brains associated with degenerative markers such as bax, intracellular A, and hyperphosphorylated tau. Thus, in DS/AD and sporadic AD brains, converging pathological mechanisms leading to chronic oxidative stress and ets-2 upregulation in susceptible neurons may result in increased vulnerability by promoting the activation of a mitochondrial-dependent proapoptotic pathway of cell death.

Key words: Down's syndrome; Alzheimer's disease; oxidative stress; apoptosis; mitochondria; ets-2

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Received Aug 8, 2004; revised January 19, 2005; accepted January 20, 2005.

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